Novel ERbeta agonists for the treatment of gliomas

描述（由申请人提供）：胶质母细胞瘤（GBM）是最恶性的原发性脑肿瘤，GBM （IV级胶质瘤）患者的生存时间约为14个月。雌激素在大脑发育和分化过程中起着至关重要的作用。流行病学和实验证据表明雌激素对脑肿瘤有抑制作用。然而，雌激素介导抗GBM的分子机制尚不清楚。雌激素的功能由两种ER亚型介导：作为肿瘤促进因子的ER¿和作为肿瘤抑制因子的ER¿。新出现的证据表明，GBM细胞表达ER¿；然而，由于缺乏机制的见解和专门针对ER¿的药物，ER¿的临床应用受到限制。近年来的研究发现，从甘草中分离得到的利尿素（LIQ）和合成的化合物LY500307 （LY）是选择性ER特异性激动剂。本提案的目的是将不断发展的科学证据和ER¿的功能作用转化为临床策略，通过使用ER¿特异性激动剂来抑制GBM。我们的中心假设是，ER激动剂通过增强ER的肿瘤抑制功能来抑制GBM的生长，ER激动剂促进胶质瘤干细胞的分化，从而提高治疗效果。我们的初步研究支持了这一假设：(1)ER介导的机制具有肿瘤抑制功能；(2) ER -受体激动剂对GBM细胞体外和体内增殖的抑制作用；(3) ER¿-激动剂上调ER¿的表达(4)ER¿-激动剂抑制胶质瘤干细胞的生长并促进其分化。为了研究提出的假设，在目标1中，我们将检验ER受体激动剂抑制GBM生长的意义和治疗效果。在目标2中，我们将确定ER激动剂抑制GBM的分子机制。在目标3中，我们将研究ER激动剂在胶质瘤干细胞分化中的作用。了解ER在GBM中作为肿瘤抑制因子的作用将有助于最大化GBM的治疗机会。由于涉及ER激动剂的概念的新颖性及其在抑制GBM方面的治疗潜力，拟议的研究具有创新性。这一建议将确立ER¿信号在GBM进展中的意义和治疗潜力，从而为使用ER¿特异性配体（LIQ和LY）来抑制GBM进展创造新的范例。由于目前临床试验中的雌激素受体激动剂耐受性良好，副作用有限，血脑屏障通透性好，因此确定雌激素受体激动剂作为一种治疗剂可以很容易地适应临床使用，作为单一疗法或与目前的化疗和放疗联合使用，从而为提高GBM患者的生存率提供了额外的工具。此外，这些研究的结果有可能在分子水平上为ER介导的肿瘤抑制机制提供新的见解。

DESCRIPTION (provided by applicant): Glioblastoma (GBM) are the most malignant primary brain tumor and patients with GBM (grade IV glioma) have a survival time of approximately 14 months. Estrogen plays a crucial role during brain development and differentiation. Epidemiological and experimental evidence suggests tumor suppressive role of estrogen on brain tumors. However, the molecular mechanisms by which estrogen mediate protection against GBM remains unknown. Estrogen functions are mediated by two ER-subtypes: ER¿ that functions as tumor promoter and ER¿ that functions as a tumor suppressor. Emerging evidence suggest that GBM cells express ER¿; however, the clinical utility of ER¿ is limited due to lack of mechanistic insights and agents that specifically target ER¿. Recent studies have identified liquiritigenin (LIQ) isolated from the plant Glycyrrhiza uralensis and synthetic compound LY500307 (LY) as selective ER¿ specific agonists. The objective of this proposal is to translate evolving scientific evidence and the functional role of ER¿ into a clinical strategy to suppress GBM by employing ER¿ specific agonists. Our central hypothesis is that ER¿ agonists inhibit the growth of GBM by enhancing tumor suppressive functions of ER¿ and that ER¿ agonists promote differentiation of glioma stem cells leading to increased therapeutic efficacy. The hypothesis is supported by our preliminary studies that (1) ER¿-mediated mechanisms play a tumor suppressive function; (2) ER¿ agonists suppress GBM cell proliferation in vitro and in vivo; (3) ER¿-agonists upregulate expression of ER¿ (4) ER¿-agonists inhibit growth of Glioma Stem Cells and promote their differentiation. To investigate the proposed hypotheses, in aim 1, we will test the significance and therapeutic efficacy of ER¿ agonists to inhibit the growth of GBM. In aim 2, we will determine the molecular mechanism(s) of ER¿ agonists in the suppression of GBM. In aim 3, we will investigate the role of ER¿ agonists in the differentiation of Glioma Stem Cells. Understanding how ER¿ functions as a tumor suppressor in GBM will be useful in maximizing treatment opportunities for GBM. The proposed research is innovative due to the novelty of the concepts involving ER¿ agonists and their therapeutic potential in the suppression of GBM. This proposal will establish the significance and therapeutic potential of ER¿ signaling in GBM progression and thus create a new paradigm for the use of ER¿ specific ligands (LIQ and LY) for curbing GBM progression. Since ER¿ agonists currently in clinical trials are well tolerated with limited side effects and good blood-brain barrier permeability, identification of ER¿ agonists as a therapeutic agent can be readily adapted to clinical use as a monotherpy or in combination with current chemotherapies and radiation, thereby providing an additional tool for enhancing survival in GBM patients. Further, the results from these studies have the potential to provide novel insights into the mechanisms of ER¿ mediated tumor suppression at the molecular level.